Methods and compositions for enantioselective oxidation reactions

ABSTRACT

This invention provides methods and catalyst systems for catalyzing enantioselective oxidation reactions, including cyclization reactions and enantioselective oxidation reactions of secondary alcohols and other similarly reactive organic substrates. Use of the methods and catalyst systems for kinetic resolution of racemic mixtures of secondary alcohols is also described.

CROSS REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of U.S. ProvisionalApplication Serial No. 60/274,642 filed Mar. 12, 2001.

FIELD OF THE INVENTION

[0002] This invention relates to a method of catalyzing enantioselectiveoxidation reactions, including cyclization reactions, and a catalystsystem for use in such reactions. More particularly, the inventionrelates to the enantioselective oxidation of an organic compound with acatalyst system to produce an oxidized organic compound and a singleenantiomer of the organic compound. The invention finds utility in theresolution of enantiomers as well as in the selective production ofcompounds useful in organic synthesis methods, as either intermediatesor final products, both of which possess commercial viability.

BACKGROUND OF THE INVENTION

[0003] Among the many hundred known processes for alcohol oxidation,comparatively few metal-catalyzed examples have been developed. Onenotable exception has been the use of catalytic palladium(II) systems,which often provide efficient oxidation of sec-alcohols to ketones inhigh yield (Blackburn et al., J. Chem. Soc., Chem. Commun. 157 (1977);Tamaru et al., Tetrahedron Lett. 20:1401 (1979); Nagashima et al., Chem.Lett. 1171 (1981); Aït-Mohand et al., Tetrahedron Lett. 36:2473 (1995);Peterson et al, J. Org. Chem. 63:3185 (1998); Nishimura et al., J. Org.Chem. 64:6750 (1999); and ten Brink et al., Science 287:1636 (2000)).Interestingly, palladium(II) oxidations have been successfullyimplemented using a wide variety of co-oxidants, including allylcarbonates, aryl halides, CCl₄, and molecular oxygen. The kineticresolution of sec-alcohols has been studied in a number of systems thatutilize chiral ligands. The exploratory studies that focused on chiralphosphine ligands in the presence of organic oxidants established thatmodest levels of asymmetric induction were attainable under a range ofconditions. However, these studies also showed that reactions carriedout under these conditions were plagued by a variety of side reactionsand inconsistencies.

[0004] Therefore, the oxidation of secondary alcohols is one of the mostcommon and well-studied reactions in chemistry. Although excellentcatalytic enantioselective methods exist for a variety of oxidationprocesses, such as epoxidation, dihydroxylation, and aziridination, itis surprising that there are relatively few catalytic enantioselectiveexamples of the ubiquitous alcohol oxidation.

[0005] Accordingly, there is a continuing need in the art for improvedenantioselective oxidation methods, as well as improved methods ofselectively oxidizing one isomer of a racemic mixture of compounds.Additionally, there is a need in the art for catalyst systems that areuseful in such methods. The present invention addresses those needs.

SUMMARY OF THE INVENTION

[0006] One aspect of the invention relates to a method of catalyzing anenantioselective oxidation reaction of an organic compound, comprising:a) contacting the organic compound with i) an oxidizing agent, and ii) acatalyst comprising a metal composition and a chiral ligand, wherein themetal is selected from the group consisting of Group 8, Group 9 andGroup 10 of the Periodic Table of the Elements; and b) producing anoxidized organic compound and a single enantiomer of the organiccompound.

[0007] Another aspect of the invention pertains to a method ofcatalyzing an enantioselective oxidative cyclization reaction of anorganic compound, comprising: a) contacting the organic compound with:i) an oxidizing agent, and ii) a catalyst comprising a metal compositionand a chiral ligand, wherein the metal is selected from the groupconsisting of Group 8, Group 9 and Group 10 of the Periodic Table of theElements; and b) producing a cyclic organic compound.

[0008] Yet another aspect of the invention relates to a catalyst systemcomprising: a) a metal composition, wherein the metal is selected fromthe group consisting of Group 8, Group 9 and Group 10 of the PeriodicTable of the Elements; and b) a chiral ligand comprising: i) at leastone chiral atom, and ii) two or more tertiary amines that are separatedby two or more linking atoms.

[0009] Still another aspect of the invention relates to a catalystsystem comprising: a) a chiral ligand having the structure:

[0010] R^(a)R^(a)N—CR^(b)R^(b)—(X)_(n)—CR^(b)R^(b)—NR^(a)R^(a)

[0011] wherein each R^(a) group is independently selected from the groupconsisting of alkyl, cycloalkyl, cycloheteroalkyl, aryl, heteroaryl andsilyl; X is —CR^(b)R^(b)— or a heteroatom; n is an integer from 0-2; andeach R^(b) group is independently selected from the group consisting ofhydrogen, alkyl, cycloalkyl, cycloheteroalkyl, aryl, heteroaryl andsilyl; and wherein two or more of the R^(a) and R^(b) groups, togetherwith the atoms to which they are attached, can be taken together to formone or more cyclic structures; complexed with b) a metal composition,wherein the metal is selected from the group consisting of Group 8,Group 9 and Group 10 of the Periodic Table of the Elements.

[0012] Still another aspect of the invention relates to a catalystsystem comprising: a) a chiral ligand having the structure:

[0013] wherein each R^(c) group is independently selected from the groupconsisting of alkyl, cycloalkyl, cycloheteroalkyl, aryl, heteroaryl andsilyl; X′ is selected from the group consisting of —O—, —S—, —N(R^(d))—,—C(R^(d))₂—, —C(O)—, —C(NR^(d))—, —C(OR^(d))₂—, and —C(SR^(d))₂—; andeach R^(d) group is independently selected from the group consisting ofhydrogen, alkyl, cycloalkyl, cyclobeteroalkyl, aryl, heteroaryl andsilyl; and wherein two or more of the R^(c) and R^(d) groups, togetherwith the atoms to which they are attached, can be taken together to formone or more cyclic structures; complexed with b) a metal composition,wherein the metal is selected from the group consisting of Group 8,Group 9 and Group 10 of the Periodic Table of the Elements.

DETAILED DESCRIPTION OF THE INVENTION

[0014] The present invention relates to methods and catalyst systems forcatalyzing enantioselective oxidation reactions, includingenantioselective oxidation reactions of secondary alcohols and othersimilarly reactive organic substrates. The methods and catalyst systemsdescribed herein are particularly useful for kinetic resolution ofracemic mixtures of enantiomers, for example secondary alcohols. As willbe described in detail below, greater than 99% enantiomeric excess ofthe unreacted alcohol can be achieved.

[0015] Before describing detailed embodiments of the invention, it willbe useful to set forth definitions that are used in describing theinvention. The definitions set forth apply only to the terms as they areused in this patent and may not be applicable to the same terms as usedelsewhere, for example in scientific literature or other patents orapplications including other applications by these inventors or assignedto common owners. The following description of the preferred embodimentsand examples are provided by way of explanation and illustration. Assuch, they are not to be viewed as limiting the scope of the inventionas defined by the claims. Additionally, when examples are given, theyare intended to be exemplary only and not to be restrictive. Forexample, when an example is said to “include” a specific feature, thatis intended to imply that it may have that feature but not that suchexamples are limited to those that include that feature.

[0016] It must be noted that, as used in the specification and theappended claims, the singular forms “a,” “an” and “the” include pluralreferents unless the context clearly dictates otherwise. Thus, forexample, reference to “a compound” encompasses a combination or mixtureof different compounds as well as a single compound, reference to“suitable solvent” includes a single such solvent as well as acombination or mixture of different solvents, and the like.

[0017] In describing and claiming the present invention, the followingterminology will be used in accordance with the definitions set outbelow.

[0018] As used herein, the term “alkyl” refers to a branched orunbranched saturated hydrocarbon group typically although notnecessarily containing about 1-24 carbon atoms, unless indicatedotherwise. Exemplary alkyl groups include methyl, ethyl, n-propyl,isopropyl, n-butyl, isobutyl, t-butyl, n-amyl, isoamyl, n-hexyl,n-heptyl, n-octyl, n-decyl, hexyloctyl, tetradecyl, hexadecyl, eicosyl,tetracosyl, and the like, as well as cycloalkyl groups such ascyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,cyclooctyl and the like. Generally, although again not necessarily,alkyl groups herein contain about 1-12 carbon atoms. The term “loweralkyl” refers to an alkyl group of 1-6 carbon atoms, preferably 1-4carbon atoms. The alkyl group is optionally substituted at one or morepositions. Exemplary substituents include but are not limited tohydroxyl, cyano, alkoxy, ═O, ═S, —NO₂, halo, heteroalkyl, amine,thioether, —SH, and aryl. Accordingly, if not otherwise indicated, theterms “alkyl” includes branched, unbranched, unsubstituted, andsubstituted alkyl groups. The term “cycloalkyl” refers to a cyclicalkyl, as defined above, and is typically a stable 3- to 7 memberedmonocyclic or 7- to 10-membered polycyclic ring which is saturated orpartially unsaturated (e. g., containing one or more double bonds).Similarly, the term “cycloheteroalkyl” is intended to mean a cyclicalkyl group, as defined above, that contains one or more heteroatoms,and is typically a stable 3- to 7 membered monocyclic or 7- to10-membered polycyclic ring which is saturated or partially unsaturatedand contains 1-4 heteroatoms (N, O, S, P or Si). As with alkyl, theterms “cycloalkyl” and “cycloheteroalkyl” are intended to include bothunsubstituted and substituted groups. The substitutions can be on acarbon or a heteroatom if the resulting compound is stable. For example,any amino group contained within the heterocycloalkyl group can be aprimary, secondary or tertiary amine, as long as the structure isstable.

[0019] As used herein, the term “aryl” is intended to mean an aromaticsubstituent containing a single aromatic ring (e.g., phenyl) or multiplearomatic rings that are fused together (e.g., naphthyl or biphenyl),directly linked, or indirectly linked (such that the different aromaticrings are bound to a common group such as a methylene or ethylenemoiety). Typically, the aryl group comprises from 5-14 carbon atoms.Preferred aryl groups contain one aromatic ring or two fused or linkedaromatic rings, e.g., phenyl, naphthyl, biphenyl, diphenylether,diphenylamine, benzophenone, and the like. The aryl moiety may beindependently substituted with one or more substituent groups, typically1-3 substituents, including ═O, —OH, —COOH, —CH₂—SO₂—phenyl, —C₁₋₆alkyl,—O—C₁₋₆alkyl, —C(O)—C₁₋₄alkyl, —(CH₂)₀₋₂—C(O)—O—C₁₋₄alkyl, cycloalkyl,—C₁₋₆alkoxy, halo, nitro, amino, alkylamino, dialkylamino,—C(O)—N(C₁₋₄alkyl)₂, —NH—C(O)—C₁₋₄alkyl, —C(O)—NH₂, —SO₂—NH₂,trifluoromethyl, cyano, aryl, benzyl, —O—aryl and —S-aryl. Thus, theterm “aryl” includes unsubstituted and substituted aryl groups. The term“heteroaryl” refer to aryl, as defined above, in which at least onecarbon atom, typically 1-3 carbon atoms, is replaced with a heteroatomN, O, S, P or Si). The heteroaryl can have the heteroatoms within asingle ring, (e.g., such as pyridyl, imidazolyl, thiazolyl, pyrimidine,oxazolyl, and the like), or within two rings (e.g., indolyl, quinolinyl,benzofuranyl, and the like). As with aryl, the term “heteroaryl” isintended to include both unsubstituted and substituted heteroarylgroups. The substitutions can be on a carbon or a heteroatom if theresulting compound is stable. For example, any amino group containedwithin the heteroaryl group can be a primary, secondary or tertiaryamine, as long as the structure is stable.

[0020] As used herein, the term “chiral ligand” is intended to mean anyligand known in the art that contains (a) at least one chiral atom and(b) two or more tertiary amines that are separated by two or morelinking atoms. A chiral ligand can exist as two enantiomers of oppositeconfiguration. One of skill in the art will appreciate that for anygiven asymmetric reaction, each enantiomer will produce products ofopposite configuration from the other, but with the same conversion andoptical purity. For purposes of illustration, the chiral ligand andproduct structures are shown herein for one enantiomer. It isunderstood, however, that the invention also pertains to thecorresponding enantiomer(s) of opposite configuration. It is furtherunderstood that one of skill in the art can readily select theappropriate enantiomer to achieve the desired product configuration.

[0021] The term “chiral catalyst” is intended to mean a catalystcomprising a metal composition and a chiral ligand, wherein the metal isselected from the group consisting of Group 8, Group 9 and Group 10 ofthe Periodic Table of the Elements.

[0022] The term “cyclic structure” is intended to include cycloalkyl,cycloheteroalkyl, aryl and heteroaryl groups, as well as fused ringsystems.

[0023] As used herein, the term “enantioselective oxidation” is intendedto mean that the reaction either selectively oxidizes one isomer of acompound contained in a racemic mixture of the compound, or produces acompound as a single enantiomer from an achiral starting material.

[0024] The term “ee” is intended to represent the percentage obtained bysubtracting the amount of the S-enantiomer from the R-enantiomer, anddividing by the sum of the amount of R-enantiomer and S-enantiomer:

[0025] The term “heteroatom” refers to nitrogen, oxygen, sulfur,phosphorus and silicon. As a linker, the heteroatom is represented by—O—, —S—, —NR—, etc. The heteroatoms can exist in their chemicallyallowed oxidation states. Thus sulfur can exist as a sulfide, sulfoxide,or sulfone.

[0026] As used herein, the term “silyl” is intended to mean a silylgroup (—SiH₃) or derivative thereof. The term silyl can thus berepresented by the formula —SiR₃, where each R group is independently H,alkyl, cycloalkyl, cycloheteroalkyl, aryl or heteroaryl.

[0027] As used herein, the term “tertiary amine” is intended to mean agroup of the formula R′—N(R″)(R′″), where R′, R″, and R′″ are the sameor different moieties and are not hydrogen.

[0028] In describing and claiming the present invention, the followingabbreviations will be used in accordance with the definitions set outbelow. ABBREVIATIONS allyl -CH₂CHCH₂ Ar aryl dba dibenzylideneacetoneEtOAc Ethyl acetate Me methyl nbd norbornadiene Ac Acetyl Ph phenyl TLCThin-layer chromatography

[0029] The invention provides for a method of catalyzing anenantioselective oxidation reaction of an organic compound, comprising:a) contacting the organic compound with i) an oxidizing agent, and ii) acatalyst comprising a metal composition and a chiral ligand, wherein themetal is selected from the group consisting of Group 8, Group 9 andGroup 10 of the Periodic Table of the Elements; and b) producing anoxidized organic compound and a single enantiomer of the organiccompound. Typically, the organic compound will be an alcohol, thiol,amine or phosphine.

[0030] In another embodiment of the invention the enantioselectiveoxidation reaction is a cyclization reaction of an organic compound.Typically, the organic compound will contain an olefin tethered to anucleophilic atom, which can be carbon or a heteroatom.

[0031] By selectively oxidizing a single enantiomer when selectivelyoxidizing a compound enantiomer, at least two products will be produced:the oxidized compound and the single enantiomer of the excess unreactedcompound. In this reaction, the percentage of enantiomer that consistsof a single enantiomer preferably is at least about 50%, more preferablygreater than 60% and most preferably greater than 90%.

[0032] The oxidized organic compound may then be reduced back to itsoriginal state and oxidized again with the catalyst system of theinvention to produce additional amounts of the single enantiomer andoxidized organic compound.

[0033] The oxidizing agent is preferably used in a stoichiometricamount.

[0034] Suitable oxidizing agents are those that effectively oxidize theorganic compound without producing undesired by-products. In addition,it is preferred to use the oxidizing agent in a stoichiometric amount.Exemplary oxidants include, by way of illustration and not limitation,molecular oxygen, benzoquinone, Cu (I) salts, and Cu (II) salts.Molecular oxygen is particularly well suited for use in the methods ofthe invention.

[0035] The organic compound may be oxidized by contacting the organiccompound with a catalyst system in a suitable organic solvent such astoluene, tert-amyl alcohol, water, CHCl₃, methylene chloride,1,2-dichloroethane, and benzene. Other suitable solvents for oxidationreactions are well known in the art.

[0036] The catalyst system of the invention is a chiral catalystcomprising a Group 8, Group 9 or Group 10 metal and a chiral ligand,preferably an enantiomerically enriched chiral ligand. One embodiment ofthe invention relates to a catalyst system comprising: a) a metalcomposition, wherein the metal is selected from the group consisting ofGroup 8, Group 9 and Group 10 of the Periodic Table of the Elements; andb) a chiral ligand comprising: i) at least one chiral atom, and ii) twoor more tertiary amines that are separated by two or more linking atoms.The catalyst systems finds particular use in enantioselective reactions,including but not limited to the enantioselective oxidation andoxidative cyclization reactions described herein.

[0037] The metal composition can comprise the metal itself or a sourceof the metal. Any metal from Group 8 (iron, ruthenium, osmium), Group 9(cobalt, rhodium, iridium) or Group 10 (nickel, palladium, and platinum)of the Periodic Table of the Elements may be used in the catalystsystem. Preferably, the metal is a Group 10 metal, more preferablypalladium. Exemplary sources of metals include complexes, such aspalladium (II) complexes. Exemplary palladium (II) complexes include, byway of illustration and not limitation, acetates such as Pd(OAc)₂ andother esters; Pd₂(dba)₃; [(allyl)PdCl]₂; halide complexes such as PdCl₂,and halide complexes with additional substituents such as Pd(CH₃CN₂)Cl₂,Pd(OCOCF₃), Pd(PhCN₂)Cl₂, PdCl₂ (cyclooctadiene) and Pd(nbd)Cl₂.

[0038] Another embodiment of the invention relates to a catalyst systemcomprising: a) a chiral ligand having the structure:

[0039] R^(a)R^(a)N—CR^(b)R^(b)—(X)_(n)—CR^(b)R^(b)—NR^(a)R^(a)

[0040] wherein each R^(a) group is independently selected from the groupconsisting of alkyl, cycloalkyl, cycloheteroalkyl, aryl, heteroaryl andsilyl; X is —CR^(b)R^(b)— or a heteroatom; n is an integer from 0-2; andeach R^(b) group is independently selected from the group consisting ofhydrogen, alkyl, cycloalkyl, cycloheteroalkyl, aryl, heteroaryl andsilyl; and wherein two or more of the R^(a) and R^(b) groups, togetherwith the atoms to which they are attached, can be taken together to formone or more cyclic structures; complexed with b) a metal composition,wherein the metal is selected from the group consisting of Group 8,Group 9 and Group 10 of the Periodic Table of the Elements.

[0041] The catalyst systems finds particular use in enantioselectivereactions, including but not limited to the enantioselective oxidationand oxidative cyclization reactions described herein.

[0042] In one preferred embodiment, n is 1.

[0043] Exemplary chiral ligands are set forth below:

[0044] R^(a)R^(a)N—CR^(b)R^(b)—CR^(b)R^(b)—NR^(a)R^(a)

[0045] R^(a)R^(a)N—CR^(b)R^(b)—(CR^(b)R^(b))—CR^(b)R^(b)—NR^(a)R^(a)

[0046]R^(a)R^(a)N—CR^(b)R^(b)—(CR^(b)R^(b)—CR^(b)R^(b))—CR^(b)R^(b)—NR^(a)R^(a)

[0047] In another preferred embodiment of the chiral ligand, n is 1 andtwo or more of the R^(a) and R^(b) groups, together with the atoms towhich they are attached, are taken together to form a four-ringstructure. One such preferred four-ring structure is (−)-sparteine.

[0048] In another embodiment of the invention, the catalyst systemcomprises: a) a chiral ligand having the structure:

[0049] wherein each R^(c) group is independently selected from the groupconsisting of alkyl, cycloalkyl, cycloheteroalkyl, aryl, heteroaryl andsilyl; X′ is selected from the group consisting of —O—, —S—, —N(R^(d))—,—C(R^(d))₂—, —C(O)—, —C(NR^(d))—, —C(OR^(d))₂—, and —C(SR^(d))₂—; andeach R^(d) group is independently selected from the group consisting ofhydrogen, alkyl, cycloalkyl, cycloheteroalkyl, aryl, heteroaryl andsilyl; and wherein two or more of the R^(c) and R^(d) groups, togetherwith the atoms to which they are attached, can be taken together to formone or more cyclic structures; complexed with b) a metal composition,wherein the metal is selected from the group consisting of Group 8,Group 9 and Group 10 of the Periodic Table of the Elements.

[0050] In one preferred embodiment, X′ is —CR^(d)R^(d) and two or moreof the R^(c) and R^(d) groups, together with the atoms to which they areattached, are taken together to form a four-ring structure. One suchstructure of the chiral ligand is (−)-sparteine.

[0051] As noted above, the invention provides for a method of catalyzingan enantioselective oxidation reaction of an organic compound,comprising: a) contacting the organic compound with i) an oxidizingagent, and ii) a catalyst comprising a metal composition and a chiralligand, wherein the metal is selected from the group consisting of Group8, Group 9 and Group 10 of the Periodic Table of the Elements; and b)producing an oxidized organic compound and a single enantiomer of theorganic compound. This method finds utility in several enantioselectiveoxidation reactions.

[0052] Performing enantioselective oxidation reactions with the chiralcatalyst of the invention has the added advantage that only one oxidantis needed. Most oxidation reactions that utilize a Group 8, 9 or 10metal catalyst include a co-oxidant to reoxidize the metal. In themethods of the invention, the oxidant (e.g., molecular oxygen) alsoserves as the co-oxidant.

Kinetic Resolution of Racemic Mixtures

[0053] In one embodiment of the invention, the enantioselectiveoxidation reaction is the kinetic resolution of a racemic mixture toprovide an enantioenriched product. Scheme I illustrates one suchreaction, where the kinetic resolution of the racemic mixture (±)-I.1provides the enantioenriched product I.1. It is understood however, thatother compounds that undergo this type of reaction can be used insteadof compound (±)-I.1.

[0054] where R¹ and R² are independently selected from the groupconsisting of alkyl, cycloalkyl, cycloheteroalkyl, aryl, heteroaryl,silyl and substituted vinyl, or R¹ and R² are taken together to form acycloalkyl; Y is selected from the group consisting of O, NR³, S andPR³; and R³is selected from the group consisting of H, alkyl,cycloalkyl, cycloheteroalkyl, aryl, heteroaryl, silyl and substitutedvinyl.

[0055] A variation on this resolution reaction is shown in Scheme II:

[0056] where R⁴, R⁵ and R⁶ are independently selected from the groupconsisting of alkyl, cycloalkyl, cycloheteroalkyl, aryl, heteroaryl,silyl and substituted vinyl; Z is selected from the group consisting ofO, NR⁷, S and PR⁷; and R⁷ is selected from the group consisting of H, H,alkyl, cycloalkyl, cycloheteroalkyl, aryl, heteroaryl, silyl andsubstituted vinyl.

[0057] In one embodiment of the invention, the racemic mixture in SchemeI is an alcohol (Y═O). The alcohol preferably has an oxidizable,secondary functional group, for example a chiral secondary alcohol. Themethod and catalyst system of the invention can be used to achieveenantiomeric excesses of the unreacted alcohol of greater than 90%. Theselective oxidation of a secondary alcohol is readily accomplished usingmolecular oxygen as the terminal oxidant, as shown in Scheme I. Apreferred solvent is toluene. An exemplary reaction is shown in SchemeIa:

Enantioselective Wacker-type Cyclization

[0058] The oxidation of ethylene to acetaldehyde, commonly referred toas the Wacker oxidation reaction (Smidt et al., Angew. Chem. 71:176(1959); Smidt et al., Angew. Chem., Int. Ed. Engl. 1:80 (19620; andSmidt, J. Chem. Ind. 54 (1962)), is one of the best-known reactionscatalyzed by palladium(II). Typically, palladium is complexed with acopper co-oxidant to re-oxidize the palladium, such as PdCl₂—CuCl₂. Thisoxidation reaction is useful in the synthetic transformation of olefins,but there has been minimal work on catalyzed enantioselectiveWacker-type cyclization reactions. See for example, Uozumi et al., J.Org. Chem. 63:5071-5075 (1998), where a Pd-boxax catalyst was used incombination with benzoquinone as the co-oxidant.

[0059] Accordingly, in one embodiment of the invention, theenantioselective oxidation reaction is an enantioselective Wacker-typecyclization reaction. Scheme III illustrates one such reaction. It isunderstood however, that other compounds that undergo this type ofreaction can be used instead of compound III.1. For example, thecompound can have one or more substitutions on the aromatic ring or thecompound may be a cycloalkyl, cycloheteroalkyl, heteroaryl or other arylring.

[0060] Performing an enantioselective Wacker-type cyclization reactionwith the chiral catalyst of the invention has the added advantage thatthe reaction can be conducted in the absence of a co-oxidant, i.e., onlyone oxidant is needed, as compared to state of the art reactions thatrequire a co-oxidant such as benzoquinone or a cupric chloride.

Enantioselective Aromatic Oxidation

[0061] In one embodiment of the invention, the enantioselectiveoxidation reaction is an enantioselective aromatic oxidation reaction.This reaction typically involves the oxidation of a hydroxymethylphenolto a spiro epoxy cyclohexidienone. Scheme IV illustrates one suchreaction. It is understood however, that other compounds that undergothis type of reaction can be used instead of compound IV.1. For example,the compound can have one or more substitutions on the aromatic ring orthe compound may be a heteroaryl or other aryl ring.

Enantio-Group Differentiation of Meso Diols

[0062] In one embodiment of the invention, the enantioselectiveoxidation reaction is the enantio-group differentiation of meso diols.Scheme V illustrates one such reaction. It is understood however, thatother meso diol compounds that undergo this type of reaction can be usedinstead of compound V.1. For example, there can be one or moresubstitutions on the cycloalkyl ring or the compound may be acycloheteroalkyl, heteroaryl, aryl or other cycloalkyl ring. Inaddition, the hydroxyl groups can be part of a cyclic ring.

[0063] Another example of an enantio-group differentiation of meso diolsis described in Example 3.

Enantioselective Oxidative [4+2] Cycloadditions

[0064] In one embodiment of the invention, the enantioselectiveoxidation reaction is an enantioselective oxidative [4+2] cycloadditionreaction. Scheme VI illustrates one such reaction. It is understoodhowever, that other compounds that undergo this type of reaction can beused instead of compound VI.1.

[0065] where —SiR₃ is a silyl group or derivative thereof, as definedabove.

C—C Bond Forming Cyclization

[0066] In one embodiment of the invention, the enantioselectiveoxidation reaction is a C—C bond forming cyclization reaction. SchemeVII illustrates one such reaction. It is understood however, that othercompounds that undergo this type of reaction can be used instead ofcompound VII.1.

[0067] where R is selected from the group consisting of H, alkyl,cycloalkyl, cycloheteroalkyl, aryl and heteroaryl.

Enantioselective Oxidative Cyclization Reactions

[0068] As noted above, the invention also provides for a method ofcatalyzing an enatioselective oxidative cyclization of an organiccompound. Exemplary cyclization reactions, as shown in Schemes VIII, IXand X. It is understood however, that other compounds that undergo thesetypes of reactions can be used instead of compounds VIII.1, IX.1 andX.1. For example, the carbon atoms in these compounds can have one ormore substituents (e.g., alkyl, cycloalkyl, cycloheteroalkyl, aryl andheteroaryl groups).

[0069] wherein R⁸, R⁹ and R¹⁰ are independently selected from the groupconsisting of H, alkyl, cycloalkyl, cycloheteroalkyl, aryl, heteroaryl,silyl and substituted vinyl; T is selected from the group consisting ofO, NR¹¹, S and PR¹¹; R¹¹ is selected from the group consisting of H,alkyl, cycloalkyl, cycloheteroalkyl, aryl, heteroaryl, silyl andsubstituted vinyl; and a is an integer from 1 to 3.

[0070] wherein R¹², R¹³ and R¹⁴ are independently selected from thegroup consisting of H, alkyl, cycloalkyl, cycloheteroalkyl, aryl,heteroaryl, silyl and substituted vinyl; T is selected from the groupconsisting of O, NR¹⁵, S and PR¹⁵; R¹⁵ is selected from the groupconsisting of H, alkyl, cycloalkyl, cycloheteroalkyl, aryl, heteroaryl,silyl and substituted vinyl; and b is an integer from 0 to 2.

[0071] wherein R¹⁶, R¹⁷ and R¹⁸ are independently selected from thegroup consisting of H, alkyl, cycloalkyl, cycloheteroalkyl, aryl,heteroaryl, silyl and substituted vinyl; T is selected from the groupconsisting of O, NR¹⁹, S and PR¹⁹; R¹⁹ is selected from the groupconsisting of H, alkyl, cycloalkyl, cycloheteroalkyl, aryl, heteroaryl,silyl and substituted vinyl; and c is an integer from 0 to 2.

[0072] In addition to the reactions illustrated above as Schemes I-X,the catalyst system of the invention finds utility in the improvedsynthesis of numerous pharmaceutical agents that have chiral centers.Such pharmaceutical agents can thus exist as a pair of enantiomers. Whenchemically synthesized, the resulting product is often a racemic mixtureso the two enantiomers, and typically only one enantiomer is opticallyactive. Thus, the product must be resolved prior to use. This additionalstep is often lengthy and can involve loss of up to half of thematerial. Thus if these pharmaceutical agents could be synthesized by anenantioselective reaction, only the optically active enantiomer would beproduced.

[0073] The following list of pharmaceutical agents and reaction steps isintended to be merely illustrative and not limiting in scope.

[0074] The traditional synthesis of pharmaceutical agents such asamosulalol, bamethan, bitolterol, denopamine, fluoxetine andisoprenaline, involves a reduction step using a Pd—C catalyst. Thetraditional synthesis of pharmaceutical agents such as epinephrine,etilefrine and mefruside, involves a reduction step using a Raney-Nicatalyst. The traditional synthesis of pharmaceutical agents such asmefloquine, involves a reduction step using a Pt catalyst. Thetraditional synthesis of pharmaceutical agents such as metaraminol,involves an reductive amination step using a Pd—C catalyst. The catalystsystem of the invention can be used in combination with any of theaforementioned catalysts to achieve a kinetic resolution of the alcohol,resulting in an enantiopure chiral drug.

[0075] The traditional synthesis of pharmaceutical agents such asclorprenaline, eprozinol, fexofenadine hydrochloride, isoconazole,mabuterol and miconazole, involves a reduction step using NaBH₄. Thecatalyst system of the invention can be used in combination with NaBH₄to achieve a kinetic resolution of the alcohol, resulting in anenantiopure chiral drug.

[0076] The catalyst system of the invention also finds utility in thesynthesis of pharmaceutical agents such as bromazine, carbocisteine,chloroamphenicol, econazole, fadrozole, fenipentol, fenticonazole,fexofenadine, fluoxitine, mefloquine, montelukast sodium, andcloperastine, whose traditional synthesis involves a step using aracemic benzylic alcohol starting material, which could undergooxidative kinetic resolution to provide enantiopure starting materialsand thus an enantiopure chiral drug.

[0077] The catalyst system of the invention also finds utility in thesynthesis of pharmaceutical agents such as chlorcyclizine,clobenztropine, whose traditional synthesis involves a step using aracemic benzylic chloride starting material, which could bealternatively prepared from the corresponding alcohol. Thus, oxidativekinetic resolution of the benzylic alcohol would provide enantiopurestarting materials and thus an enantiopure chiral drug.

EXAMPLES

[0078] The practice of the present invention will employ, unlessotherwise indicated, conventional techniques of pharmaceuticalformulation, medicinal chemistry, and the like, which are within theskill of the art. Such techniques are explained fully in the literature.Preparation of various types of pharmaceutical formulations aredescribed, for example, in Remington: The Science and Practice ofPharmacy, Nineteenth Edition. (1995) cited supra and Ansel et al.,Pharmaceutical Dosage Forms and Drug Delivery Systems, 6^(th) Ed.(Media, PA: Williams & Wilkins, 1995).

[0079] The following examples are put forth so as to provide those ofordinary skill in the art with a complete disclosure and description ofhow to make and use the compounds of the invention, and are not intendedto limit the scope of what the inventors regard as their invention.Efforts have been made to ensure accuracy with respect to numbers (e.g.,amounts, temperature, etc.) but some errors and deviations should beaccounted for. Unless indicated otherwise, parts are parts by weight,temperature is in ° C. and pressure is at or near atmospheric. Allcomponents were obtained commercially unless otherwise indicated.

Materials and Methods

[0080] Unless stated otherwise, reactions were performed in flame-driedglassware under a nitrogen or an argon atmosphere, using freshlydistilled solvents. All other commercially obtained reagents were usedas received. Reaction temperatures were controlled by an IKAmagtemperature modulator. TLC was performed using E. Merck silica gel 60F254 precoated plates (0.25 mm). ICN Silica gel (particle size0.032-0.063 mm) was used for flash chromatography. ¹H and ¹³C NMRchemical shifts are reported relative to Me₄Si (δ0.0). Analytical chiralHPLC was performed on a Chiralcel OJ, AS, or OD-H column (each is 4.6mm×25 cm) obtained from Daicel Chemical Industries, Ltd. Analyticalachiral GC was performed using an Agilent DB-WAX (30.0 m×0.25 m) column.Analytical chiral GC was carried out using a Chiraldex B-DM column (30.0m×0.25 mm) purchased from Bodman Industries. Commercially availableracemic alcohols in Table 3 (entries 1, 2, 3, 5, 7, 8, and 9) werepurchased from the Sigma-Aldrich Chemical Company (Milwaukee, Wis.).Non-commercially available racemic alcohols used in Table 3(corresponding to entries 4, 6, and 10) were prepared as described inRuble et al., J. Am. Chem. Soc. 119:1492 (1997) and Ruble et al., J.Org. Chem. 63:2794 (1998). Commercially available samples of enantiopurealcohols for analytical comparison purposes (entries 1, 4, 7, 8, and 9)were also purchased from the Sigma-Aldrich Chemical Company.Non-commercially available enantiopure alcohols were prepared bypalladium-catalyzed oxidative kinetic resolution (Table 3 entries 2[Nakamura et al J. Chem. Soc., Perkin. Trans. 1:2397.3 (1999)], 3[Nieduzak et al., Tetrahedron: Asymmetry 2:113.4 (1991)], 5 [Bakker etal., Tetrahedron: Asymmetry 11: 1801.5 (2000)], 6 [Nakamura et al., J.Org. Chem. 63:8957.6 (1998)] and 10 [Argus et al., J. Chem. Soc. 1195(1960)]) were compared by optical rotation to known values.

Example 1 General Procedure for the Oxidative Kinetic Resolution ofSecondary Alcohols Ligand and Palladium Source Screening Trials

[0081] A 25 mL Schlenk flask equipped with a magnetic stir bar wascharged with powdered molecular sieves (MS3 Å, 0.25 g) and flame-driedunder vacuum. After cooling under dry N₂, Pd complex (0.025 mmol, 0.05equiv) was added followed by toluene (5.0 mL), and an appropriate ligand(0.10 mmol, 0.20 equiv). For experiments which probed the effect of thechiral ligand, the appropriate ligand was used in the same generalprocedure with Pd(OAc)₂ (Reaction 1). For experiments that probed theeffect of the palladium source, the appropriate Pd complex was used inthe same general procedure (Reaction 2). The structures of all chiralligands tested are provided below:

[0082] Using 1-phenylethanol (±)-I1.1 as the alcohol, the conditionsdeveloped by Uemura (Nishimura et al., J. Org. Chem. 64:6750-6755(1999)), incorporated herein by reference, were used to test a varietyof chiral ligands. The flask was vacuum evacuated and filled with O₂(3×, balloon), and the reaction mixture was heated to 80° C. for 10 min.The alcohol (±)-I1.1 (0.50 mmol, 1.0 equiv) was introduced and thereaction monitored by standard analytical techniques (TLC, GC, ¹H-NMR,and HPLC) for % conversion and enantiomeric excess values. Aliquots ofthe reaction mixture (0.2 mL) were collected after 24 h, 40 h, 72 h, 96h, 120 h, and 144 h depending on the course of the reaction (typicallythree aliquots per run). Each aliquot was filtered through a small plugof silica gel (EtOAc eluent), evaporated and analyzed. Percentconversions were measured by GC integration of the alcohol and theketone peaks, correcting for response factors.

[0083] After testing many structurally diverse ligands (shown above) inthe oxidation reaction, (−)-sparteine emerged as a preferred ligand, asshown in Table 1: TABLE 1 Ligand Screen for the Pd-Catalyzed OxidativeKinetic Resolution of 1-Phenylethanol Entry Ligand Time Conversion eeROH^(a) s^(b) 1 (S,S)-Ph-PYBOX 72 h   2% — 1 2 (R)-BINAP 24 h 29.0%   0%1 3 (−)-cinchonidine 72 h   2% — 1 4 (−)-brucine 24 h 77.0%   0% 1 5(DHQ)₂PHAL 24 h 31.6%  8.7% 1.6 6 (−)-sparteine 24 h 15.1% 13.7% 8.8

[0084] The nature of the palladium source was found to be critical (seeTable 2 for conversion rates).

[0085] It was found that substituting PdCl₂ for Pd(OAc)₂ induced amarked increase in the selectivity factor(s). For example, oxidativekinetic resolution of 1-phenylethanol (±)-2.1 using Pd(OAc)₂ proceededwith a selectivity factor of 8.8, whereas the analogous resolution usingPdCl₂ was found to have a selectivity factor of 16.3, thereby providingacetophenone in 62.6% conversion and unreacted alcohol of 98.0% ee.Further screening of the palladium source resulted in the discovery thatPd(nbd)Cl₂ provided an even more active catalytic system (Table 2, entry7, s=23.1). TABLE 2 Importance of the Palladium Source for the OxidativeKinetic Resolution of 1-Phenylethanol Entry Pd source Time Conversion eeROH^(a) s^(b) 1 Pd(OAc)₂ 24 h 15.1% 13.7% 8.8 2 Pd₂(dba)₃ 55 h 66.2%81.5% 5.7 3 PdCl₂ 96 h 62.6% 98.0% 16.3 4 Pd(CH₃CN₂)Cl₂ 36 h 51.7% 79.8%16.5 5 Pd(PhCN₂)Cl₂ 36 h 57.4% 92.1% 16.9 6 [(allyl)PdCl]₂ 96 h 60.2%96.9% 18.0 7 Pd(nbd)Cl₂ 96 h 59.9% 98.7% 23.1

General Procedure for the Oxidative Kinetic Resolution of SecondaryAlcohols Preparative Runs (6.0 mmol in Table 3)

[0086] A 200 mL flask equipped with a magnetic stir bar was charged withpowdered molecular sieves (MS3 Å, 3.0 g) and flame-dried under vacuum.After cooling under dry N₂, Pd(nbd)Cl₂ (80.8 mg, 0.30 mmol, 0.05 equiv)was added followed by toluene (60.0 mL), and (−)-sparteine (276 μL, 1.20mmol, 0.20 equiv). The flask was vacuum evacuated and filled with O₂(3×, balloon), and the reaction mixture was heated to 80° C. for 10 min.The racemic alcohol (6.00 mmol, 1.0 equiv) was introduced and thereaction monitored by standard analytical techniques (TLC, GC, ¹H-NMR,and HPLC) for % conversion and enantiomeric excess values. Aliquots ofthe reaction mixture (0.2 mL) were collected after 24 h, 40 h, 72 h, 96h, 120 h, and 144 h depending on the course of the reaction (typicallythree aliquots per run). Each aliquot was filtered through a small plugof silica gel (EtOAc eluent), evaporated and analyzed. Upon completionof the reaction, the reaction mixture was filtered through a pad of SiO₂(EtOAc eluent) and purified by column chromatography on SiO₂.

General Procedure for the Oxidative Kinetic Resolution of SecondaryAlcohols Preparative Runs (8.0 mmol in Table 3)

[0087]

[0088] A 200 mL flask equipped with a magnetic stir bar was charged withpowdered molecular sieves (MS3 Å, 4.0 g) and flame-dried under vacuum.After cooling under dry N₂, Pd(nbd)Cl₂ (108 mg, 0.40 mmol, 0.05 equiv)was added followed by toluene (80.0 mL), and (−)-sparteine (368 μL, 1.60mmol, 0.20 equiv). The flask was vacuum evacuated and filled with O₂(3×, balloon), and the reaction mixture was heated to 80° C. for 10 min.The alcohol (±)-3.1 (8.00 mmol, 1.0 equiv) was introduced and thereaction monitored by standard analytical techniques (TLC, GC, ¹H-NMR,and HPLC) for % conversion and enantiomeric excess values. Aliquots ofthe reaction mixture (0.2 mL) were collected after 24 h, 40 h, 72 h, 96h, 120 h, and 144 h depending on the course of the reaction (typicallythree aliquots per run). Each aliquot was filtered through a small plugof silica gel (EtOAc eluent), evaporated and analyzed. Upon completionof the reaction, the reaction mixture was filtered through a pad of SiO₂(EtOAc eluent) and purified by column chromatography on SiO₂.

[0089] As shown in Table 3, palladium-catalyzed kinetic resolutions with(−)-sparteine as a ligand provide uniformly excellent levels ofasymmetric induction with a variety of activated alcohols (i.e.,benzylic and allylic). Benzylic alcohols with functionalized aromaticrings serve particularly well as substrates for oxidative kineticresolution, with selectivity factors as high as 32 (entries 1-7).Additionally, the resolution is not limited to 1-substituted ethanolderivatives (entries 7-9). Substrates containing fused ring systems arealso resolved to high levels of enantiopurity (entries 8 and 9, ee>93%).Importantly, the potential utility and versatility of the catalyticoxidative kinetic resolution is further established by the reaction of asubstituted allylic alcohol (entry 10). In all cases, the absolutestereoconfiguration of the enantioenriched alcohol could be determinedby comparison to data from known optically pure substance as wasconsistent with that shown in Table 3.

[0090] Data for the following racemic alcohols (±)-3.1 is shown Table 3:

[0091] Data for the unreacted alcohols 3.1 (major enantiomers) is alsopresented in Table 3. The unreacted alcohols have the followingstructures, with the numbers corresponding to the equivalent racemicalcohol shown above:

[0092] The chromatography eluent for Entries 1-6, 8 and 10 was 6:1→3:1hexanes/EtOAc. The chromatography eluent for Entry 7 was 6:1→4:1hexanes/EtOAc and the chromatography eluent Entry 9 was 9:1→4:1hexanes/EtOAc. TABLE 3 The Oxidative Kinetic Resolution of SecondaryAlcohols Isolated yield Isolated yield Entry Amount Time C of ketone ROHee ROH^(b) s^(c,d) 1 0.977 g  96 h 59.9% 0.535 g 0.366 g 98.7% 23.1 (8.00 mmol) (56%) (37%) 2  1.22 g  96 h 66.6% 0.773 g 0.392 g 98.1%12.3  (8.00 mmol) (64%) (32%) 3  1.12 g  54 h 63.3% 0.623 g 0.361 g97.4% 14.4  (8.00 mmol) (56%) (32%) 4  1.03 g 192 h 55.9% 0.555 g 0.443g 78.4% 9.8  (6.00 mmol) (54%) (43%) 5  5.00 g 112 h 55.2%  2.75 g  2.20g 99.0% 47.1 (29.00 mmol) (55%) (44%) 6  1.09 g 144 h 48.4% 0.492 g0.533 g 68.7% 13.1  (8.00 mmol) (46%) (49%) 7  1.09 g 192 h 59.3% 0.625g 0.435 g 93.1% 14.8  (8.00 mmol) (58%) (40%) 8  1.07 g    54 h^(e)67.5% 0.662 g 0.323 g 93.4% 8.3  (8.00 mmol) (63%) (30%) 9  1.19 g  40 h68.6% 0.796 g 0.370 g 99.8% 15.8  (8.00 mmol) (68%) (3 1%) 10 0..973 g120 h 70.4% 0.671 g 0.286 g 91.8% 6.6  (6.00 mmol) (70%) (29%) #measuredby GC using a DB-WAX column.

Example 2 Scale-up Procedure for the Oxidative Kinetic Resolution ofα-Methyl-2-Naphthalenemethanol (4.1): 1^(st) Cycle

[0093] Particularly noteworthy is the preparative reaction shown inReaction 4. The oxidative kinetic resolution performed well on multigramscale with good recovery (44%) of optically enriched alcohol (−)-4.1 in99% ee. Quantitative reduction of ketone 4.2 provides an opportunity forthe preparation of chiral alcohol (−)-4.1 in >50% overall yield from aracemic mixture via multiple oxidative kinetic resolution cycles.

[0094] A 500 mL round bottom flask was charged with powdered molecularsieves (MS3 Å, 14.5 g) and a magnetic stir bar and flame-dried undervacuum. After cooling under dry N₂, Pd(nbd)Cl₂ (0.391 g, 1.45 mmol, 0.05equiv) was added followed by toluene (290 mL,), and (−)-sparteine (1.34mL, 5.81 mmol, 0.20 equiv). The flask was vacuum evacuated and filledwith O₂ (3×, balloon), and the reaction mixture was heated to 80° C. for10 min. Alcohol (±)-4.1 (5.00 g, 29.0 mmol, 1.0 equiv) was introducedand the reaction mixture heated at 80° C. for 112 h. Progress of thereaction was monitored by standard analytical techniques (TLC, GC,¹H-NMR, and HPLC) for % conversion and enantiomeric excess values by theremoval of small aliquots of the reaction mixture (0.2 mL) which werefiltered through silica gel (EtOAc eluent), evaporated and analyzed.After the reaction rate had significantly slowed (112 h, 55%conversion), and aliquot analysis showed high levels of enantiocontrolfor the remaining alcohol (−)-4.1 (99.0% ee), the entire reactionmixture was filtered through a small column of silica gel (5×6 cm, EtOAceluent). The filtrate was evaporated and purified by flashchromatography on silica gel (6:1→3:1 hexanes/EtOAc eluent) to provideketone 4.2 (R_(F)=0.56, 2.75 g, 55% yield) and alcohol (−)-4.1(R_(F)=0.44, 2.20 g, 44% yield, 99.0% ee) as white solids.

Regeneration of Alcohol ((±)-4.1)

[0095] A cooled (0° C.) solution of ketone 4.2 (2.75 g, 16.2 mmol, 1.0equiv) in 1:1 CH₂Cl₂/MeOH (16.2 mL) was treated with NaBH₄ (733 mg, 19.4mmol, 1.2 equiv) in four portions over 10 min. The reaction was stirredat 0° C. for 15 min, and treated with 1 N HCl solution (30 mL) slowlyover 15 min. After the evolution of gas was complete, the layers wereseparated, and the aqueous layer extracted with CH₂Cl₂ (3×30 mL). Thecombined organic layers were dried over MgSO₄, evaporated, and purifiedby flash chromatography on silica gel (3:1 hexanes/EtOAc eluent) toprovide alcohol (±)-4.1 (2.76 g, 99% yield) as a white solid, which wasused in cycle two.

2^(nd) Cycle

[0096] A 500 mL round bottom flask was charged with Molecular Sieves(MS3 Å, 8.0 g) and flame-dried under vacuum. After cooling under dry N₂,Pd(nbd)Cl₂ (0.216 g, 0.800 mmol, 0.05 equiv) was added followed bytoluene (160 mL), and (−)-sparteine (0.735 mL, 3.20 mmol, 0.20 equiv).The flask was vacuum evacuated and filled with O₂ (3×, balloon), and thereaction mixture was heated to 80° C. for 10 min. Alcohol (±)-4.1 (2.76g, 16.0 mmol, 1.0 equiv) prepared above was introduced and the reactionmixture heated at 80° C. for 96 h. Progress of the reaction wasmonitored by standard analytical techniques (TLC, GC, ¹H-NMR, and HPLC)for % conversion and enantiomeric excess values by the removal of smallaliquots (0.2 mL) which were filtered through silica gel (EtOAc eluent),evaporated and analyzed. After the reaction rate had significantlyslowed (81 h, 55% conversion), and aliquot analysis showed high levelsof enantiocontrol for the remaining alcohol (−)-4.1 (99.0% ee), theentire reaction mixture was filtered through a small column of silicagel (5×6 cm, EtOAc eluent). The filtrate was evaporated and purified byflash chromatography on silica gel (6:1→3:1 hexanes/EtOAc eluent) toprovide ketone 4.2 (1.43 g, 54% yield) and alcohol (−)-4.1 (1.20 g, 44%yield, 99.0% ee) as white solids. The combination of both cyclesprovided alcohol (−)-4.1 (3.39 g, 68% yield, 99.0% ee).

Example 3 Oxidative Desymmetrization of Meso Diol

[0097]

[0098] A 50 mL Schlenk flask equipped with a magnetic stir bar wascharged with Molecular Sieves (MS3 Å, 625 mg) and flame-dried undervacuum. After cooling under dry N₂, Pd(nbd)Cl₂ (16.8 mg, 0.0625 mmol,0.05 equiv) was added followed by toluene (12.5 mL), and (−)-sparteine(57 μL, 0.25 mmol, 0.20 equiv). The flask was vacuum evacuated andfilled with O₂ (3×, balloon), and the reaction mixture was heated to 80°C. for 10 min. Diol 5.1 (205 mg, 1.25 mmol, 1.0 equiv; prepared asdescribed in Yamada et al., J. Org. Chem. 64:9365 (1999)) was introducedand the reaction monitored by standard analytical techniques (TLC, GC,¹H-NMR, and HPLC) for % conversion and enantiomeric excess values. Uponcompletion of the reaction, the reaction mixture was filtered through apad of SiO₂ (EtOAc eluent) and purified by column chromatography on SiO₂(3:1→1:1 hexane/EtOAc eluent) to provide hydroxyketone (+)-5.2 as an oil(145 mg, 72% yield, 95% ee); [α]D²³+19.6 (c 1.0, MeOH).

[0099] All patents, publications, and other published documentsmentioned or referred to in this specification are herein incorporatedby reference in their entirety.

[0100] It is to be understood that while the invention has beendescribed in conjunction with the preferred specific embodiments hereof,the foregoing description, as well as the examples which are intended toillustrate and not limit the scope of the invention, it should beunderstood by those skilled in the art that various changes may be madeand equivalents may be substituted without departing from the scope ofthe invention. Other aspects, advantages and modifications will beapparent to those skilled in the art to which the invention pertains.

[0101] Accordingly, the scope of the invention should therefore bedetermined with reference to the appended claims, along with the fullrange of equivalents to which those claims are entitled.

We claim:
 1. A method of catalyzing an enantioselective oxidationreaction of an organic compound, comprising: a) contacting the organiccompound with: i) an oxidizing agent, and ii) a catalyst comprising ametal composition and a chiral ligand, wherein the metal is selectedfrom the group consisting of Group 8, Group 9 and Group 10 of thePeriodic Table of the Elements; and b) producing an oxidized organiccompound and a single enantiomer of the organic compound.
 2. The methodof claim 1 wherein the organic compound is selected from the groupconsisting of alcohols, thiols, amines and phosphines.
 3. The method ofclaim 1 wherein the oxidizing agent is selected from the groupconsisting of molecular oxygen, benzoquinone, Cu (I) salts, and Cu (II)salts.
 4. The method of claim 3 wherein the oxidizing agent is molecularoxygen.
 5. The method of claim 1 wherein the oxidizing agent is used ina stoichiometric amount.
 6. The method of claim 1 which is conducted inan organic solvent selected from the group consisting of toluene,tert-amyl alcohol, water, CHCl₃, methylene chloride, 1,2-dichloroethane,and benzene.
 7. The method of claim 1 wherein the metal is palladium. 8.The method of claim 7 wherein the metal composition is a palladium (II)complex.
 9. The method of claim 8 wherein the palladium (II) complex isselected from the group consisting of Pd(OAc)₂,Pd₂(dibenzylideneacetone)₃, PdCl₂, Pd(CH₃CN₂)Cl₂, Pd(PhCN₂)Cl₂,[(allyl)PdCl]₂, PdCl₂ (cyclooctadiene), Pd(OCOCF₃), andPd(norbomadiene)Cl₂.
 10. The method of claim 1 wherein the chiral ligandis (−)-sparteine.
 11. The method of claim 1 where the percentage ofenantiomer that consists of the single enantiomer is at least about 50%.12. The method of claim 11 where the percentage of enantiomer is greaterthan 60%.
 13. The method of claim 12 where the percentage of enantiomeris greater than 90%.
 14. The method of claim 1 wherein theenantioselective oxidation reaction is the kinetic resolution of aracemic mixture.
 15. The method of claim 14 wherein the enantioselectiveoxidation reaction is the kinetic resolution of racemic alcohols. 16.The organic compound of claim 15 wherein the organic compound is analcohol with an oxidizable, secondary functional group.
 17. The organiccompound of claim 16 which is a chiral secondary alcohol.
 18. The methodof claim 1 wherein the enantioselective oxidation reaction is anenantioselective Wacker-type cyclization reaction.
 19. The method ofclaim 1 wherein the enantioselective oxidation reaction is anenantioselective aromatic oxidation reaction.
 20. The method of claim 1wherein the enantioselective oxidation reaction is the enantio-groupdifferentiation of meso diols.
 21. The method of claim 1 wherein theenantioselective oxidation reaction is an enantioselective oxidative[4+2] cycloaddition reaction.
 22. The method of claim 1 wherein theenantioselective oxidation reaction is a C—C bond forming cyclizationreaction.
 23. The method of claim 1 wherein the enantioselectiveoxidation reaction is a cyclization reaction.
 24. The method of claim 23wherein the organic compound contains an olefin tethered to anucleophilic atom.
 25. A catalyst system comprising: a) a metalcomposition, wherein the metal is selected from the group consisting ofGroup 8, Group 9 and Group 10 of the Periodic Table of the Elements; andb) a chiral ligand comprising: i) at least one chiral atom, and ii) twoor more tertiary amines that are separated by two or more linking atoms.26. The catalyst system of claim 25 wherein the chiral ligand is(−)-sparteine.
 27. The catalyst system of claim 25 wherein the metal ispalladium.
 28. The catalyst system of claim 25 wherein the metalcomposition is a palladium (II) complex.
 29. The catalyst system ofclaim 28 wherein the palladium (II) complex is selected from the groupconsisting of Pd(OAc)₂, Pd₂(dba)₃, PdCl₂, Pd(CH₃CN₂)Cl₂, Pd(PhCN₂)Cl₂,[(allyl)PdCl]₂ and Pd(norbomadiene)Cl₂.
 30. A catalyst systemcomprising: a) a chiral ligand having the structure:R^(a)R^(a)N—CR^(b)R^(b)—(X)_(n)—CR^(b)R^(b)—NR^(a)R^(a) wherein: eachR^(a) group is independently selected from the group consisting ofalkyl, cycloalkyl, cycloheteroalkyl, aryl, heteroaryl and silyl; X is—CR^(b)R^(b)— or a heteroatom; n is an integer from 0-2; and each R^(b)group is independently selected from the group consisting of hydrogen,alkyl, cycloalkyl, cycloheteroalkyl, aryl, heteroaryl and silyl; andwherein two or more of the R^(a) and R^(b) groups, together with theatoms to which they are attached, can be taken together to form one ormore cyclic structures; complexed with b) a metal composition, whereinthe metal is selected from the group consisting of Group 8, Group 9 andGroup 10 of the Periodic Table of the Elements.
 31. The catalyst systemof claim 30 wherein n is
 1. 32. The catalyst system of claim 31 whereintwo or more of the R^(a) and R^(b) groups, together with the atoms towhich they are attached, are taken together to form a four-ringstructure.
 33. The catalyst system of claim 32 wherein the chiral ligandis (−)-sparteine.
 34. The catalyst system of claim 30 wherein the metalis palladium.
 35. The catalyst system of claim 30 wherein the metalcomposition is a palladium (II) complex.
 36. The catalyst system ofclaim 35 wherein the palladium (II) complex is selected from the groupconsisting of Pd(OAc)₂, Pd₂(dibenzylideneacetone)₃, PdCl₂,Pd(CH₃CN₂)Cl₂, Pd(PhCN₂)Cl₂, [(allyl)PdCl]₂, PdCl₂ (cyclooctadiene),Pd(OCOCF₃), and Pd(norbomadiene)Cl₂.
 37. A catalyst system comprising:a) a chiral ligand having the structure:

wherein each R^(c) group is independently selected from the groupconsisting of alkyl, cycloalkyl, cycloheteroalkyl, aryl, heteroaryl andsilyl; X′ is selected from the group consisting of —O—, —S—, —N(R^(d))—,—C(R^(d))₂—, —C(O)—, —C(NR^(d))—, —C(OR^(d))₂—, and —C(SR^(d))₂—; andeach R^(d) group is independently selected from the group consisting ofhydrogen, alkyl, cycloalkyl, cycloheteroalkyl, aryl, heteroaryl andsilyl; and wherein two or more of the R^(c) and R^(d) groups, togetherwith the atoms to which they are attached, can be taken together to formone or more cyclic structures; complexed with b) a metal composition,wherein the metal is selected from the group consisting of Group 8,Group 9 and Group 10 of the Periodic Table of the Elements.
 38. Thecatalyst system of claim 37 wherein X′ is —CR^(d)R^(d), and two or moreof the R^(c) and R^(d) groups, together with the atoms to which they areattached, are taken together to form a four-ring structure.
 39. Thecatalyst system of claim 38 wherein the chiral ligand is (−)-sparteine.40. The catalyst system of claim 37 wherein the metal is palladium. 41.The catalyst system of claim 37 wherein the metal composition is apalladium (II) complex.
 42. The catalyst system of claim 41 wherein thepalladium (II) complex is selected from the group consisting ofPd(OAc)₂, Pd₂(dibenzylideneacetone)₃, PdCl₂, Pd(CH₃CN₂)Cl₂,Pd(PhCN₂)Cl₂, [(allyl)PdCl]₂, PdCl₂ (cyclooctadiene), Pd(OCOCF₃), andPd(norbomadiene)Cl₂.